“We now have a wealth of well-established processes in place to support our ongoing research and have proven its success.”
Konrad Mostert, Stellenbosch University, South Africa
The problem
Antimicrobial resistance (AMR) is a global health1 and economic threat2 that requires the development of new antimicrobial drug classes with novel targets. Only a handful of new drug classes have been developed in recent times. This has increased the burden of common community- and hospital acquired infections (HAI) caused by high-priority pathogens which are resistant to several first line antibiotics, such as Staphylococcus aureus (S. aureus).
Developing countries in Africa bear the biggest burden of the negative effects of AMR. In 2019, sub-Saharan Africa had the highest mortality rate (23.5 deaths per 100,000) attributable to AMR compared to other regions3. One of the biggest challenges for African researchers to tackle AMR is a lack of sustainable resources. This includes financial and technical resources, as well as access to world class research facilities and equipment.
The challenge
Target based drug discovery is a constant back and forth to progress from ‘hit’ screening to developing lead compounds. An abundance of resources is required to screen many potential chemical compounds against a validated protein drug target, a process that involves large compound libraries and the development and use of high-throughput assays.
Specialised, expensive equipment and reagents determine if a screened compound inhibits or binds to a target protein, while additional resources are required to synthesise and improve hit compounds into lead compounds suitable for further drug development. Without such resources, African-based researchers face severe obstacles to employing well-established drug discovery approaches such as X-ray crystallography at synchrotrons for target-based drug discovery.
The solution
The development of novel antimicrobials against organisms such as S. aureus is a key aim of researchers at Stellenbosch University’s Strauss Laboratory in South Africa. The goal is to target enzymes involved in the biosynthesis and utilisation of coenzyme A – a central metabolic cofactor – as well as other enzymes involved in providing S. aureus with resistance against the human body’s natural defence systems.
The AMR drug discovery process has been fast-tracked at the Strauss Laboratory due to funding from Grand Challenges Africa: Drug Discovery and with grants through the GCRF START and START: Health & Bio Science programmes. This has supported vital skills training and access to the world class fragment-based X-ray crystallography screening platform – XChem – at Diamond Light Source, the UK’s national synchrotron. This novel screening technique not only allows scientists to directly determine if screened fragments bind to the target; it also enables them to determine the interaction with the target, providing invaluable information to further enhance the binding and inhibiting capabilities of these fragments. The whole process is ultra-fast, making it possible to screen hundreds of fragments a day. Hundreds to thousands of these datasets are required to help understand what compounds can bind to the proteins, which then inform chemists to design lead compounds which are early precursors of drugs which could act on that protein.
Impact
As a result of access to XChem and regular beamtime at Diamond, multiple compound libraries have been screened and hits to more promising lead compounds have progressed. More than 1000 fragments and 1000 follow-up compounds have been screened in a handful of research visits to Diamond. If screening just used existing equipment in South Africa, only 112 screened crystals could be completed and shipped to Diamond – every three to four months – for further study, significantly slowing the research.
The GCRF START grant, which funded the initial research, was a springboard between 2018 and 2021 to Grand Challenges Africa funding, which has made the continuation of this research possible. Subsequent funding by START: Health & Bio Science has allowed the Strauss Laboratory to employ Konrad Mostert as a Postdoctoral Research Fellow and has covered his research visits to Diamond. Grand Challenges Africa also funded vital lab equipment including an Opentrons pipetting robot which makes it possible to synthesise large libraries of additional follow-up compounds at the Strauss Laboratory for testing at XChem.
Capacity building
Funding grants have provided researchers and students in the Strauss Laboratory with world class skills, access to experts and mentors, and the opportunity to share skills and knowledge with students from across Africa. This will benefit another generation of future African X-ray crystallographers and is a step towards the sustainable continuation of START’s goals, including growing Structural Biology and synchrotron techniques across the continent.
In one example, START members funded by the GCRF START grant, established a crystallisation platform at the Strauss Laboratory, which enabled Konrad Mostert to build on and continue this legacy. Konrad is relatively new to the Structural Biology field. His recent visit to the XChem research facilities at Diamond accompanied by MX BAG training, has developed his skills to maintain and use the crystallisation platform at the Strauss Laboratory as a valuable tool for drug discovery research in South Africa. Konrad will share this knowledge and experience with Strauss Laboratory colleagues who hail from a range of African countries, and with university teaching staff, such as Dr Tawanda Zininga, who will in turn be able to pass this knowledge to many other students.
“The African Continent is the only remaining continent (apart from Antarctica) without a synchrotron light source. Yet African scientists require access to these types of world class facilities to do fundamental and proof of concept research, not only outcome-driven research. We need investment from START: Health and Bio Sciences and others to continue to provide African scientists with beamtime and access to enable our projects and collaborations to evolve into sustainably funded projects. We now have a wealth of well-established processes in place to support our ongoing research and have proven its success. Ongoing funding is vital to maintain these highly fruitful connections and the use of world-leading synchrotrons like Diamond for Africa’s benefit and beyond.”
Konrad Mostert, Stellenbosch University, South Africa
References
1 Antimicrobial resistance (who.int) accessed 11.3.2023
2 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext accessed 12.3.2023
3 Kariuki S, Kering K, Wairimu C, Onsare R, Mbae C. Antimicrobial Resistance Rates and Surveillance in Sub-Saharan Africa: Where Are We Now? Infect Drug Resist. 2022 Jul 7;15:3589-3609. doi: 10.2147/IDR.S342753. PMID: 35837538; PMCID: PMC9273632.